New FDA Guidance Aims to Ease Approval for New NGS Tests—But It Probably Won’t Work

Test makers have long complained about the FDA’s unwillingness to embrace technology and diagnostics advances. But on April 13, the agency took steps to address those concerns by issuing a pair of final guidances designed to make the process for securing approval of new next-generation sequencing (NGS) tests faster, quicker and easier. Here is the lowdown on each guidance and what it might portend for NGS test development going forward.

Guidance 1: Use of Public Genetic Variant Repositories to Show Clinical Validity

The first final guidance, which bears the catchy title “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic & Genomic-Based In Vitro Diagnostics,” explains how NGS test developers can rely on FDA-recognized public genetic variant repositories to support the accuracy of their tests and related marketing claims.

A “genetic variant database” means a publicly accessible database of human genetic variants that aggregates and curates reports of human genotypephenotype relationships to a disease or condition with publicly available documentation of evidence supporting those linkages, the guidance explains. While following an open-access model is a best practice for databases that may be used to support clinical validity of genetic or genomic tests, the guidance adds that databases which use licensing models and charge fees for commercial use may also qualify for such uses.

The guidance lists the criteria of reliability for a genetic variant database. It should:

• Operate so as to provide sufficient information and assurances regarding the quality of source data and its evidence review and variant assertions;
• Offer transparency regarding its data sources and operations, particularly on how variant evidence is evaluated;
• Collect, store and report data and conclusions in compliance with all applicable requirements regarding protected health information, patient privacy, research subject protections and data security; and
• House genetic variant information generated by validated methods.

Guidance 2: Design of NGS Tests for Diagnosing Germline Diseases

The other final guidance (“Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing–Based In Vitro Diagnostics Intended to Aid in the Diagnosis of Suspected Germline Diseases”) explains to test developers the types of data the FDA is looking for in premarket submissions for such tests.

The guidance then lists recommendations covering different aspects of NGS test development and quality including:

• NGS test design considerations;
• Test performance and accuracy;
• Test run quality metrics;
• Performance and evaluation studies;
• Supplemental procedures;
• Variant annotation and filtering;
• Presentation of test performance in labeling; and
• Test reports.

Why Guidance Probably Won’t Have Much Practical Impact on NGS Test Development

The self-stated objective of the guidance is to “help ensure patients receive accurate, reliable, and clinically meaningful test results, while promoting innovation in test development.” According to Jeffrey Shuren MD, director of the FDA’s Center for Devices and Radiological Health, the new final guidance on genetic variant databases “will change the paradigm” of NGS development “by encouraging data sharing and the accumulation in public databases of evidence supporting the clinical validity of genomic tests to help provide an even more efficient path to market.”

But while certainly well-intentioned and constructive, the new guidances will have a hard time living up to the “paradigm changing” expectation that FDA officials are fostering.

Too Limited in Scope

For one thing, the guidances apply to new tests that are undergoing premarket review. But premarket review is not required to secure FDA approval of lab developed tests (LDTs). Accordingly, NGS test makers typically treat their NGS-based tests as LDTs to get around the need for premarket review. Result: The guidance will have minimal practical impact on LDTs development, at least for the near future.

The related problem is that the guidance expressly excludes many kinds of NGS-based tests, including:

• Companion or complementary diagnostic testing;
• Cell-free DNA testing;
• Microbial infection diagnosis;
• Microbial genome identification;
• Detection of antimicrobial resistance and virulence markers;
• Pre-implantation embryo testing; and
• RNA sequencing.